This proposal outlines a 5-year plan for the career development of Kevin Whitehead to build upon his research training received as a Pfizer postdoctoral research fellow and to facilitate his transition to independence and excellence in the field of vascular developmental biology. Dean Li, MD, PhD, Associate Professor of Medicine, a recognized leader in the field of vascular developmental biology, will serve as sponsor. Additional scientific and career advice will be obtained from co-sponsor Guy Zimmerman, Professor of Medicine and chair of the program in Human Molecular Biology and Genetics (HMBG) and a recognized expert in vascular cell biology, integrins and selectins. This work will be done in collaboration with Douglas Marchuk, Associate Professor of Genetics at Duke University, and Antonio Duarte, Auxiliary Professor at the Faculty of Veterinary Medicine in Lisbon, Portugal. In addition, a scientific advisory committee will be formed to provide scientific and career advice. Previous work demonstrated an important role in arterial development for Ccm1, a gene responsible for a subset of CCM cases in humans. Proposed research will address the hypothesis that arterial development requires the expression of Ccm1, Ccm2 and Ccm3. Specific aims include: 1) Describe the first developmental role of CCM genes by studying null mutants. 2) Determine the cellular basis for vascular defects, by studying conditional mutants with neural or endothelial mutations of the CCM genes. 3) Describe the cellular basis of CCM gene function by examining the endothelial cell culture phenotype resulting from a lack of CCM gene expression in endothelial cells or adjacent neural cells. The University of Utah provides an ideal environment for the proposed research career award. The University of Utah has excellent core facilities and a rich history of gene targeting in mice. The Division of Cardiology has a strong commitment to developing young academic faculty, and the HMBG program is unique in acting as an interface between basic and clinical science and has provided an ideal environment for the professional development of physician scientists such as Dr. Whitehead.